Structures of two melanoma-associated antigens suggest allosteric regulation of effector binding

Joseph A. Newman, Christopher D O Cooper, Anette K. Roos, Hazel Aitkenhead, Udo C T Oppermann, Hearn J. Cho, Roman Osman, Opher Gileadi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE-A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is predominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders.

LanguageEnglish
Article numbere0148762
Number of pages20
JournalPLoS One
Volume11
Issue number2
Early online date24 Feb 2016
DOIs
Publication statusPublished - 24 Feb 2016

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Allosteric Regulation
Melanoma-Specific Antigens
melanoma
antigens
Antigens
neoplasms
Tumors
Neoplasms
Proteins
proteins
Genes
ubiquitin-protein ligase
Ubiquitin-Protein Ligases
Oncology
Human Genome
crystal structure
Germ Cells
Binders
Plasticity
Testis

Cite this

Newman, J. A., Cooper, C. D. O., Roos, A. K., Aitkenhead, H., Oppermann, U. C. T., Cho, H. J., ... Gileadi, O. (2016). Structures of two melanoma-associated antigens suggest allosteric regulation of effector binding. PLoS One, 11(2), [e0148762]. https://doi.org/10.1371/journal.pone.0148762
Newman, Joseph A. ; Cooper, Christopher D O ; Roos, Anette K. ; Aitkenhead, Hazel ; Oppermann, Udo C T ; Cho, Hearn J. ; Osman, Roman ; Gileadi, Opher. / Structures of two melanoma-associated antigens suggest allosteric regulation of effector binding. In: PLoS One. 2016 ; Vol. 11, No. 2.
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Newman, JA, Cooper, CDO, Roos, AK, Aitkenhead, H, Oppermann, UCT, Cho, HJ, Osman, R & Gileadi, O 2016, 'Structures of two melanoma-associated antigens suggest allosteric regulation of effector binding', PLoS One, vol. 11, no. 2, e0148762. https://doi.org/10.1371/journal.pone.0148762

Structures of two melanoma-associated antigens suggest allosteric regulation of effector binding. / Newman, Joseph A.; Cooper, Christopher D O; Roos, Anette K.; Aitkenhead, Hazel; Oppermann, Udo C T; Cho, Hearn J.; Osman, Roman; Gileadi, Opher.

In: PLoS One, Vol. 11, No. 2, e0148762, 24.02.2016.

Research output: Contribution to journalArticle

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